acuity timing

8/14/2019 Acuity Timing

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Gregg W. Stone MD

for the ACUITY Investigators

Prospective, Randomized Comparison of

Routine Upfront Initiation Versus Selective

Use of Glycoprotein IIb/IIIa Inhibitors inPatients With Acute Coronary Syndromes:

The ACUITY Timing Trial


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Disclosure

Gregg W. Stone

Consultant to The Medicines Company


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Background I

Optimal management of ACS1,2

consists of anearly invasive strategy for moderate-high risk pts,

followed by revascularization with PCI or CABG Median time to cath 21 hours3

55% PCI, 12% CABG, 33% medical mgt3

GP IIb/IIIa inhibitors are a class I indication1,2

(and are used in 80% of pts during PCI of

ACS

3

) Guidelines recommend that they be administered

either upstream in all pts (PRISM PLUS and

PURSUIT), or their use may be deferred for selective

administration in the cath lab only for PCI1 Braunwald et al JACC 2002; 2 Bertrand et al. EHJ 2002; 3www.crusade.org


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Background II

However, the combination of invasiveprocedures with GP IIb/IIIa inhibitors, aspirin,

clopidogrel, and antithrombin medications

results in a high rate of hemorrhagic

complications

The upstream use of GP IIb/IIIa inhibitors

in all patients may further increase bleeding

Whether upstream GP IIb/IIIa use reducesischemic complications sufficiently to justify

such an increase is unknown


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The Question to Answer

When seeing a patient in the emergencydepartment with moderate-high risk ACS

in whom an invasive strategy is planned:

Should GP IIb/IIIa inhibitors be startedimmediately? Or

Should their use be withheld to

First perform coronary arteriography

And then only start GP IIb/IIIa inhibition if PCI

is performed?


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In moderate-high risk patients with ACS undergoingan invasive strategy, compared to the routine

upstream use of GP IIb/IIIa inhibitors in all patients,

withholding upfront GP IIb/IIIa use for deferred

administration in the cath lab only to patientsundergoing PCI will result in:

Similar 30 day rates of death, MI or unplanned

revascularization for ischemia

Reduced rates of major bleeding complications

Improved cost-effectiveness

Optimal Timing of GPI in ACS: Hypotheses


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Moderate-

high risk

ACS

Study Design First Randomization

Angiographywithi

n72h

Aspirin in allClopidogrel

dosing and timing

per local practice

UFH orEnoxaparin+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

BivalirudinAlone

R*

*Stratified by pre-angiography thienopyridine use or administration

Moderate-high risk unstable angina or NSTEMI

undergoing an invasive strategy (N = 13,800)

ACUITY Design. Stone GW et al. AHJ 2004;148:76475

Medical

management

PCI

CABG


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Moderate-

high risk

ACS

Study Design Second Randomization





dosing and timing

per local practice

BivalirudinAlone

UFH or Enoxaparin

Routine upstream

GPI in all pts

GPI started in

CCL for PCI only

R

Bivalirudin

R

Routine upstream

GPI in all pts

GPI started in

CCL for PCI only

UFH,E

noxaparin,

orB

ivalirudin

Routine upstream

GPI in all pts

Deferred GPI

for PCI only

VS.

Primary analysis

Secondary

analysis


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Major Entry Criteria

Age 18 years

Chest pain 10 within 24h

At least one of:

New ST depression ortransient ST elevation 1 mm

Troponin I, T, or CKMB Documented CAD

All other 4 TIMI risk criteria

- Age 65 years- Aspirin within 7 days

- 2 angina episodes w/i 24h

- 3 cardiac risk factors

Written informed consent

Inclusion Criteria Exclusion Criteria

No angiography within 72h

Acute STEMI or shock

Bleeding diathesis or major

bleed within 2 weeks Platelet count 100,000/mm3

INR >1.5 control

CrCl 30 ml/min

2 prior LMWH doses

Any prior abciximab

Prior tirofiban or eptifibatideif unable to be d/c for 4 hrs

Allergy to drugs, contrast




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3 Primary Endpoints (at 30 days)

1. Composite net clinical benefit =

2. Ischemic composite

3. Major bleedingor

Death from any cause

Myocardial infarction- During medical Rx: Any biomarker elevation >ULN

- Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves

- Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves

Unplanned revascularization for ischemia


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3 Primary Endpoints (at 30 days)

1. Composite net clinical benefit =

2. Ischemic composite

3. Major bleedingor

Non CABG related bleeding

- Intracranial bleeding or intraocular bleeding- Intracranial bleeding or intraocular bleeding

--Retroperitoneal bleedingRetroperitoneal bleeding

--Access site bleed requiring intervention/surgeryAccess site bleed requiring intervention/surgery

--Hematoma 5 cmHematoma 5 cm

--HgbHgb 3g/dL with an overt source or3g/dL with an overt source or4g/dL w/o overt source4g/dL w/o overt source--Blood product transfusionBlood product transfusion

Reoperation for bleeding


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Power analysis and statisticsRoutine upstream GP IIb/IIIa inhibition (n=4,600) vs.

deferred GP IIb/IIIa inhibition in the CCL for PCI only(n=4,600) The trial was powered to demonstrate non-inferiority for the composite

ischemic endpoint at 30 days between the 2 groups (treatment strategy)

1-sided upper bound of the confidence interval of the observed

difference was used for non-inferiority ( = 0.025, =25%) 2-sided confidence intervals used for superiority testing ( = 0.05)

85% power for

non-inferiority5.9%5.9%

Ischemic

composite

Power

Deferred PCI

GP IIb/IIIa

N = 4,600

Routine

upstream

GP IIb/IIIa

N = 4,600

Anticipated

30-day event

rates


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ACUITY Enrollment

USA (246)

Canada (26)

(17) Australia

(25) Spain

(8) France(12) UK

(4) Norway

Finland (3)

Poland (1)

Germany (66)

Austria (4)

(4) Netherlands

(5) Belgium

Italy (15)

Sweden (6)

(4) New Zealand

(5) Denmark

13,819 pts randomized at 448 centers in 17 countries


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7851 (56.8%) USA

438 (3.2%) Canada

499 (3.6%)Australia

547 (4.0%)Spain

155 (1.1%)France162 (1.2%)UK

89 (0.6%) Norway

Finland 51 (0.4%)

Poland 14 (0.1%)

Germany 2561 (18.5%)

Austria 356 (2.6%)

132 (1.0%) Netherlands

198 (1.4%) Belgium

Italy 238 (1.7%)

Sweden 175 (1.3%)

203 (1.5%)New Zealand

150 (1.1%) Denmark

ACUITY Enrollment13,819 pts randomized at 448 centers in 17 countries


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Moderate-

high risk

ACS

(n=13,819)

Study Design Second Randomization





dosing and timing

per local practice

BivalirudinAlone

(n=4,612)

UFH or Enoxaparin

Routine upstream

GPI in all pts

GPI started in

CCL for PCI only

R

Bivalirudin

R

Routine upstream

GPI in all pts

GPI started in

CCL for PCI only

UFH,E

noxaparin,

orBivalirudin

Routine upstream

GPI in all pts

(4,605)

Deferred GPI

for PCI only

(n=4,602)

VS.


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Baseline Characteristics

5.7%6.0%Renal insufficiency

17.2%18.4%Prior CABG

38.3%38.4%Prior PCI

57.4%57.2%Hyperlipidemia

67.0%67.0%Hypertension

9.0%8.1%- Insulin requiring

31.7%30.4%Prior MI

29.8%28.5%Current smoker

28.6%27.6%Diabetes

69.9%70.6%Male

63 [21-92]

Deferred PCI

GP IIb/IIIa(N=4,602)

63 [21-95]

Routine Upstream

GP IIb/IIIa

(N=4,605)

Age (median [range], yrs


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Baseline High Risk Features

TIMI Risk Score

70.6%70.7%Biomarker or ST

15.4%16.1%- Low (0-2)

29.1%30.3%- High (5-7)

55.5%53.7%- Intermediate (3-4)

22.4%21.7%Biomarker + ST 35.5%35.1%- ST-segment 57.6%

Deferred PCI


57.4%

Routine Upstream


- Biomarker +


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Invasive Management

Actual procedure

6.2 (2.1-23.2)6.2 (2.1-23.1)Rand. to angio/interv (h)

19.6 (7.1-29.0)19.7 (6.8-28.4)Adm. to angiography (h)

33.3%31.6%- Medical therapy

11.1%11.6%- CABG55.6%56.7%- PCI

99.0%

Deferred PCI

GP IIb/IIIa

(N=4,602)

98.9%

Routine Upstream

GP IIb/IIIa

(N=4,605)

Angiography performed


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Study Medications: GP IIb/IIIa Inhibitors

55.7%98.3%Overall exposure

Study GP IIb/IIIa PCI patients

Study GP IIb/IIIa All patients

96.2%99.3%Overall exposure

6.1%95.3%Initiated pre angiography94.0%98.8%Any use during PCI

4.6 (1.7-19.8)*0.6 (0.3-1.0)Rand. to GP IIb/IIIa (h)

2.0%0.2%Initiated post PCI

7.6%8.1%Pre randomization

5.8%94.5%Initiated pre angiography

Deferred PCI


Routine Upstream

GP

IIb/IIIa

(N=4,605)

*In PCI pts only; In a few patients the timing onset was not known


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GP IIb/IIIa Selection

N=4,339 N=212

Initiated Pre Angio (%)

Routine Upstream GP IIb/IIIa

0.4

65.2

34.4

Use During PCI (%)

N=2,559 N=2,405

Routine Upstream GP IIb/IIIa

33.5

65.4

1.1

Deferred PCI GP IIb/IIIa

4.5

62.1

33.4

Deferred PCI GP IIb/IIIa

7.6

48.6

43.8

Abciximab Eptifibatide Tirofiban


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Primary Endpoint Measures

11.7%

7.1%6.1%

4.9%

11.7%

7.9%

Net clinical

outcome

Ischemic composite Major bleeding

30dayevents(%)

Routine Upstream IIb/IIIa (N=4605) Deferred PCI IIb/IIIa (n=4602)

Routine Upstream IIb/IIIa vs. Deferred PCI IIb/IIIa

PNI


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11.7%11.7% 1.00 (0.89-1.11)


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Components of the Ischemic Composite

7.1%

1.3%

4.9%

2.1%2.8%

5.0%

7.9%

1.5%

Ischemic

composite

Death Myocardial

infarction

Unplanned

revasc for

ischemia

30dayevents(%)

Routine Upstream IIb/IIIa (N=4605) Deferred PCI IIb/IIIa (n=4602)

PSup = 0.13 PSup = 0.48 PSup = 0.70 PSup = 0.03



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Ischemic Composite Endpoint

CumulativeE

vents(%)

Days from Randomization

0

5

10

15

0 5 10 15 20 25 30 35

Estimate

7.1%Routine Upstream IIb/IIIa (N=4605)

Deferred PCI IIb/IIIa (n=4602) 7.9%P

(log rank)= 0.14



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Major Bleeding (Primary Endpoint)

0.0094.9%6.1%Major bleeding (ACUITY scale)

0.260.0%0.1% Reoperation for bleed

0.052.3%3.0% Blood transfusion

0.232.0%2.4%- hematoma 5 cm

0.620.4%0.4%- requiring intervention/surgery

0.362.4%2.7% Access site

0.020.6%1.0% Hgb 4 g/dL w/o overt source 0.091.8%2.3% Hgb 3 g/dL with overtsource

0.570.5%0.6% Retroperitoneal

1.00.0%0.0% Intraocular

0.41

P value

0.08%

Deferred PCI

GP IIb/IIIa

(N=4,602)

0.04%

Routine Upstream

GP IIb/IIIa

(N=4,605)

Intracranial


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Bleeding Endpoints (Non-CABG)

0.05


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0 1 2

Actual ManagementRoutine Upfront IIb/IIIa vs. Deferred PCI IIb/IIIa

Deferred PCI GPI better Routine Upstream GPI better

P Pint

0.34

1.06 (0.93-1.22) 0.38

0.85 (0.65-1.12) 0.25

0.96 (0.72-1.29) 0.80

0.15

1.19 (1.00-1.42) 0.05

0.88 (0.65-1.18) 0.39

1.39 (0.91-2.12) 0.13

0.74

0.84 (0.69-1.02) 0.08

0.74 (0.40-1.34) 0.33

DeferredIIb/IIIa

14.5%

15.8%

5.5%

9.5%

13.5%

3.3%

6.5%

3.3%

2.6%

UpstreamIIb/IIIa

13.7%

18.5%

5.8%

8.0%

15.3%

2.4%

7.8%

4.5%

3.7% 0.70 (0.47-1.05) 0.09

RR (95% CI)

PCI (n=5170)

CABG (n=1048)

Medical (n=2989)

Major Bleeding

Risk ratio95% CI

Net Clinical Outcome

Composite Ischemic

PCI (n=5170)

CABG (n=1048)

Medical (n=2989)

PCI (n=5170)

CABG (n=1048)

Medical (n=2989)


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Composite Ischemic - Timing Analysis

Short

(19.7 hrs)

5.6% 5.2%

9.9%

7.3% 6.7%

9.3%

0%

5%

10%

15%

20%

25%

30dayeve

nts(%)

Routine Upstream GPI (N=4605) Deferred PCI GPI (n=4602)

Median: 30.0 hrs6.1 hrs1.5 hrs

P = 0.08P = 0.06 P = 0.60

Randomization to Angio/Intervention within Index Hospitalization


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CumulativeE

vents(%)


Net Clinical Outcome Composite Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Estimate P(log rank)11.7%Routine Upstream IIb/IIIa (N=4605)

Deferred PCI IIb/IIIa (n=4602) 0.8811.7%Bivalirudin alone (N=4612) 0.00910.1%

Upstream IIb/IIIa vs. Deferred IIb/IIIa vs. Bivalirudin alone


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Ischemic Composite Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Estimate P(log rank)7.1%

0.147.9%Bivalirudin alone (N=4612) 0.287.8%

Upstream IIb/IIIa vs. Selective IIb/IIIa vs. Bivalirudin alone

CumulativeE

vents(%)

Routine Upstream IIb/IIIa (N=4605)

Deferred PCI IIb/IIIa (n=4602)


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Major Bleeding Endpoint

0

5

10

15

0 5 10 15 20 25 30 35

Estimate P(log rank)6.1%

0.0094.9%Bivalirudin alone (N=4612)


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Clinical Implications

In pts with moderate-high risk ACS undergoingan early invasive strategy, compared to the

routine upstream use of GP IIb/IIIa inhibitors in all

pts, withholding upfront IIb/IIIa inhibitor use for

selective initiation in the cath lab only to ptsundergoing PCI results in:

Similar rates of adverse ischemic events,

though a slight increase cannot be excludedReduced rates of major and minor bleeding


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Clinical Implications

The implications of these results will be furtherexamined through detailed angiographic

analysis, long-term clinical follow-up (to 1-year)

and formal cost-effectiveness analysis

Regardless, in the context of the entire ACUITY

trial, both upstream and selective GP IIb/IIIa

inhibitor strategies (with either UFH, enoxaparin

or bivalirudin) provided inferior net clinicaloutcomes compared to use of bivalirudin alone

acuity timing

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